Process for the preparation of 4-hydroxy-3-(5-methyl-3-isoxazolycarbamoyl)-2-methyl-2h-1,2-benzothiazine 1,1-dioxide

ABSTRACT

A process for the production of the compound of the formula:   piperidi IS DESCRIBED. This process comprises treating compound I:   with phosgene and triethylamine to form the compound enamineacid chloride. This enamine-acid chloride is treated with 3amino-5-methylisoxazole to give the corresponding enamine-amide, followed by hydrolysis to give the above described compound.

United States Patent 91 [1-11 3,821,211

Sircar et al. 1*June 28, 1974 PROCESS FOR THE PREPARATION OF formula:

4-HYDROXY-3-(5-METHYL-3- ISOXAZOLYCARBAMOYL)-2-METHYL-2H- 1, Z-BENZOTHIAZINE 1,1-DIOXIDE [75] Inventors: Jagadish C. Sircar, Dover; Harold l-coNH Il- LOH:

Zinnes, Rockaway; John Shavel, Jr., N Mendham, all of N]. \s/

[73] Assignee: Warner-Lambert Company, Morris Plains, NJ.

[ Notice: The portion of the term of this is described patent subsequent to Apr. 30, 1991, I has been disclaimed This process comprises treating compound I:

22 Filed: Mar. 10, 1972 211 App]. No.: 233,712 N [52] US. Cl. 260/243 R, 424/246 [51] Int. Cl C07d 93/02 58 Field of Search 260/243 R Norn S [56] References Cited UNITED STATES PATENTS 3.704.298 l l/l972 Zinnes et al. 260/243 with phosgene and triethylamlne to form the comp M Ford pound enamine-acid chloride. This enamine-acid Attorney, Agent, or Firm A1b6rt Graddis; Frank chloride is treated with 3-amino-5-methylisoxazole to Chow; Anne Kelly give the corresponding enamine-amide, followed by hydrolysis to give the above described compound.

[57] ABSTRACT A process for the production of the compound of the 2 Claims, N0 Drawings PROCESS FOR THE PREPARATION OF 4-HYDROXY-3-(5-METHYL-3- ISOXAZOLYCARBAMOYL)-2-METHYL-2H-l Z-BENZOTHIAZINE l l DIOXIDE The present invention is concerned with a novel process and, more particularly, the present invention is concerned with the production of 4-hydroxy-3-(5- methyl-3-isoxazolylcarbamoyl)-2-methyl-2l-l-l ,2- benzothiazine 1,1-dioxide having the following structural formula:

As disclosed in our copending application, Ser. No. 1 19,967 filed March 1, 1971 now abandoned, this compound exhibits antiinflammatory activity and is a desirable therapeutic agent for the treatment of certain inflammatory conditions.

According to the present invention a new and different process is described for the production of this compound. Broadly speaking, this process is represented by EXAMPLE 1 u NCH! N 2-Methyl-N-(5-methyl-3-isoxa2olyl)-4-( lpyrrolidinyl )-2H- 1 ,2-benzothiazine-3-carboxamide l ,l-dioxide A solution of 2.5 g. (0.025 mole) of phosgene in 23 ml. of benzene was diluted with 50 ml. of dry tetrahy-' the following schematic diagram:

Referring to the above diagram, compound I is treated with phosgene and triethylamine at a low temperature such as from --40 to -55 C. in an inert solvent to form enamine-acid chloride II. The resulting compound ll is treated with 3-amino-5-methylisoxazole to give the enamine-amide III which is readily hydrolyzed under acidic conditions to give the desired compound IV. v a

The starting compound I is prepared as described by Zinnes, et al. in the Journal of Organic Chemistry 31, 162 (I966).

The intermediate compound ill, in addition to being useful as an intermediate for production of the desired compound lV, also exhibits anti-inflammatory activity. For example, in the carrageenin test in rats it is effective at a dose of about 100 mg/kg.

The method as to how to use compound W is fully described in said copending application.

To further illustrate the practice of this invention, the following examples are included:

EXAMPLE 2 4-H d -3-(5- rh ]-3 i l l b l).2- with phosgene and triethylamine to form the enuminemethyI-ZH-l ,2-benzothiazine l,l-dioxide acid hl0ride having the formula:

A solution of L2 g. of unrecrystallized 2-methyl-N- (-methyl-3-isoxazolyl-4-( l-pyrrolidinyl )-2H- 1 ,2- benzothiazine-3-carboxamide l.l-dioxide in 30 ml. of 5 N/ glacial acetic acid was heated on a steam bath and 30 ml. of l N hydrochloric acid was added.- Heating was' com continued for 45 minutes during which time some of the product separated from solution. The reaction mixture was diluted with ice-water to a volume of 300 ml. and filtered to give 1.0 g. (97%) of material, m.p. H

H Substance prepared by the reaction of 3 carbethoxy 4 methylisoxazole to glve the enamme-amlde havmg the hydroxy-Z-methyl-ZH-1,2-benzothiazine 1,1-dioxide 5 formula:

with 3-amino-5-methylisoxazole. 1

We claim: i 1. A process for the production of the compound of f the formula: v

i V 7 0 and hydrolyzing said enamine-amide III to IV by the use of aqueous acid.

2. A compound of the formula:

NCH. L 7| [L which comprises treating a compound of the formula:

UNITED STATES PATENT OgFICE CERTIFICATE OF CORRECTION Patent 3.821.211 Dated June 28%1974 Inventor(s) JAGADISH c. SIRCAR, ET AL.

It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, Line 19, cancel "abandoned" and insert "u. s. Patent 3,787,324."

Signed and sealed this 29th day of October 1974.

(SEAL) Attestl McCOY M. GIBSON JR. C. MARSHALL DANN Attesting Officer Commissioner of Patents USCOMM-DC 6O376-P69 U. 5. GOVERNMENT PRINTING OFFICE: 1969 0-366-334 FORM PO-105O (10-69) 

2. A compound of the formula: 